Lithium amide addition Asymmetric

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

The catalytic asymmetric Mannich reaction of lithium enolates with imines was reported in 1997 using an external chiral ligand [36]. First, it was found that reactions of lithium enolates with imines were accelerated by addition of external chiral ligands. Then, it was revealed that reactions were in most cases accelerated in the presence of excess amounts of lithium amides. A small amount of a chiral source was then used in the asymmetric version [(Eq. (8)], and chiral ligands were optimized to achieve suitable catalytic turnover [37]. 

Several asymmetric 1,2-additions of various organolithium reagents (methyllithium, n-butyllithium, phenyllithium, lithioacetonitrile, lithium n-propylacetylide, and lithium (g) phenylacetylide) to aldehydes result in decent to excellent ee% (65-98%) when performed in the presence of a chiral lithium amido sulfide [e.g. (14)], 75 The chiral lithium amido sulfides invariably have exhibited higher levels of enantioselectivity compared to the structurally similar chiral lithium amido ethers and the chiral lithium amide without a chelating group. 

Asymmetric Aldol Reactions. Lithium enolates, derived from an ester, and LDA react with aldehydes enantioselectively in the presence of the chiral amide 2 (eq 3). When benzaldehyde is employed, the major diastereomer is the anrt-aldol with 94% ee, while the minor yn-aldol is only 43% ee. In this reaction, the lithium amide 2 coordinates to an additional lithium atom. There are four additional examples of aldehydes with the same ester enolate. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

There are several examples of the effect of LiX on enolate aggregation leading to increased enantiomeric excess in asymmetric chemical events. Koga and co-workers developed an efficient enantioselective benzylation of the lithium enolate of 19 by using a stoichiometric amount of chiral ligand 22 with LiBr in toluene [50]. The chiral lithium amide 22 was prepared by treatment of a mixture of the corresponding amine 21 and LiBr in toluene with a solution of n-BuLi in hexane. Sequential addition of ketone 19 and benzyl bromide gave rise to 20 in 89 % yield and 92 % ee. The amount... 

Application of the prolinol-derived lithium amide 11 (Scheme 9)in the asymmetric synthesis of (-F)-confertin was successful with the addition of isoprope-nyllithium to 2-methylcyclopentenone being a key step [37]. 

Two further contributions illustrate how chiral lithium amides can be used as catalysts in asymmetric deprotonation reactions (Schemes 2 and 3). The first example of catalytic chiral lithium amide chemistry was reported [13] by Asami (Scheme 2). In this process an achiral base, in this case LDA, provides a stoichiometric reservoir of amidoli-thium reagent. However, deprotonation of the epoxide is affected primarily by the chiral lithium amide 11 rather than the relative excess of LDA. Turnover is possible since the resulting chiral secondary amine 10 can be deprotonated by the remaining reservoir of LDA thus regenerating the chiral base 11. For example, the deprotonation of cyclohexene oxide 8 in the presence of DBU as an additive gives the allylic alcohol 9 in 74 % ee (82 % yield) using 50 mol% of chiral base 11. 

Note added in proof. Complexes between MeLi and Chiral 3-aminopyrrolidine lithium amides bearing a second asymmetric center on their lateral amino group have been studied using multinuclear low-temperatme NMR spectroscopy, and a relationship between the topology of these complexes and the sense of induction in the enantioselective alkylation of aaromatic aldehydes by alkyllithiums has been proposed [115], 1,2-Amino sulfides have been used as chiral ligands in the enantioselective addition of BuLi and MeLi to various aldehydes (PhCHO, EtCHO) at low temperatures in up to 98.5% ee [16],... 

In an effort to develop a more efficient method to S5mthesize enantioenriched allylic amine substrates for [2,3]-rearrangements, Davies and Smyth reported an asymmetric conjugate addition with chiral lithium amide 74 tScheme 1S.16T ° The resulting aminoester 75 was reduced to alcohol 76, which was treated with m-CPBA to furnish chiral amine iV-oxide 77. 

The answer suggests the Michael-type asymmetric addition of an enantiopure amine or its more reactive anion to enone to 23b. The authors used a lithium amide reagent for the addition to obtain the key chiral intermediate 23c (Scheme 3.9) [14]. The selected (S)-configuration of the phenyl ethylamino unit in the chiral amide anion induces the (7 )-configuration in the precursor of —)- R)-sitagliptin. 

The preparation of enantiopure or enriched complexes possessing planar chirality has been accomplished either by resolution of racemic mixtures or by asymmetric syntheses. Reported methods for the resolution of planar chirality include both chemical and kinetic resolution procedures, whilst reported asymmetric syntheses of enantiomerically pure or enriched benchrotrenic complexes include enantioselective ort/io-deprotonations with chiral lithium amide bases, and the transfer of side chain chirality onto the arene ring mediated by diastereoselective orf/io-nucleophilic additions and o/tfeo-metalations. 

Other electrophiles, such as Michael acceptors, can also be involved in the a-alkylation step. This has been exploited in the conjugate addition of enantiopure lithium amides 60 to unsaturated esters 61, followed by trapping of the resulting enolate with alkylidene malonates. This constitutes a useful methodology for the asymmetric synthesis of p-amino-a-substituted carboxylic acid derivatives 62 (Scheme 11.24) [65]. 

Abraham, E., Brock, E.A., Candela-Lena, J.I., Davies. S.G., Georgiou, M., Nicholson, R.L., Perkins, J.H., Roberts, P.M., Russell, A.J., Sanchez-Femandez, E.M., Scott, P.M., Smith, A.D., and Thomson, J. E. (2008) Asymmetric synthesis of N,0,0,0-tetra-acetyl o-lyxo-phytosphingosine, jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylUne via lithium amide conjugate addition. Org. Biomol. Chem., 6,1665—1673. 

In addition to altering the (EIZ) isomer ratio of enolates, HMPA has a noticeable effect on the metalation of imines and their subsequent alkylation (eq 9). When the metalation (by s-Butyllithium) of an asymmetric imine is performed in THF, a subsequent alkylation gives about a 1 1 mixture of regioisomers. In the presence of HMPA, however, only the regioisomer due to alkylation at the less-substituted site was observed. A synthetically useful solvent effect for HMPA is also observed in the asymmetric synthesis of trimethylsilyl enol ethers by chiral lithium amide bases. The asymmetric induction in THF can be greatly improved by simply adding HMPA as a cosolvent. 

Davies pioneered a versatile method to prepare chiral /S-amino ester derivatives through diastereoselective conjugate additions of chiral amines onto unsaturated esters [33, 101]. Conjugate addition of lithium amide 103 to acceptor 102 thus afforded an adduct in 82 % yield, and after hydrogenolytic cleavage of the N-benzyl group this provided -amino ester 104 in >98% ee [102]. Such asymmetric amide additions have been demonstrated to have wide substrate scope with respect to the substituents that may be employed on the a,y5-unsaturated esters [33]. 

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